The long-term goal of the proposed studies is to understand the cell and molecular diversity of extraocular muscle (EOM) in health and disease and establish the mechanisms that contribute toward eye muscle sparing or targeting in neuromuscular disorders. Specific Aims 1 and 2 address the origins of the EOM phenotype through manipulations of potential regulatory mechanisms at key times in development. The hypothesis that expression of the EOM-specific myosin is extrinsically regulated requiring signaling mechanisms unique to oculomotor motoneurons will be tested using conventional microscopy and sophisticated cell and molecular biology techniques. Tissue-specific regulatory mechanisms are highly pertinent since mutations may contribute toward EOM-specific disorders. The strategy of disrupting or uncoupling sensory-motor interactions during development also is used to examine modulation of the EOM phenotype by the developing visual and vestibular sensory systems that drive eye movements. Specific Aims 3 and 4 represent an important new step toward linking features of this unique phenotype to disease mechanisms. Much of our knowledge of the responsiveness of skeletal muscle to neurogenic or myogenic disease is based upon information from a limb muscle prototype. Disease states interact with well-characterized muscle fiber types to produce patterned pathological changes that are reliably used in diagnosis. Fundamental differences in the EOM phenotype provide a basis for differential response in disease. Specific Aim 3 analyzes (a) morphopathologic changes to better understand the mechanisms responsible for and adaptive changes subsequent to human congenital fibrosis of EOM and (b) a transgenic mouse model with maldevelopment of some oculomotor motoneuron pools to better understand the etiology of and muscle consequences in Duane's retraction syndrome. Preliminary studies have shown that EOM exhibits constitutively high antioxidant capacity. Specific Aim 4 tests the hypothesis that high antioxidant enzyme activity is an important factor in the resistance of EOM to dystrophinopathies. Free radicals are a final common pathway for neuron and muscle pathology in a variety of diseases and insults. Consequently, the relative protection of EOM seen in a variety of insults may be, at least in part, the result of efficient free radical scavenging mechanisms. Taken together, knowledge of EOM properties and adaptive/maladaptive responses in disease will provide a mechanistic understanding of ocular motility disorders that occur in isolation from or in conjunction with those of other skeletal muscles.